Multi-spectral fluorescence for in-vivo determination of proton energy and range in proton therapy

ABSTRACT

The accuracy charged-particle beam trajectories used for radiation therapy in patients is improved by providing feedback on the beam location within a patient&#39;s body or a quality assurance phantom. Particle beams impinge on a patient or phantom in an arrangement designed to deliver radiation dose to a tumor, while avoiding as much normal tissue as can be achieved. By placing fiducial markers in the tumor or phantom that contain specific atomic constituents, a detection signal consisting of atomic fluorescence is produced by the particle beam. An algorithm can combine the detected fluorescence signal with the known location of the fiducial markers to determine the location of the particle beam in the patient or phantom.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No.61/676,673, filed Jul. 27, 2012, which is hereby incorporated herein byreference in its entirety.

TECHNICAL FIELD

The disclosure relates to a method and apparatus for improving theaccuracy of delivery of charged-particle beams for the treatment ofcancer. The disclosure also includes an improved method for performingquality-assurance measurements on charged-particle beams used intherapy.

BACKGROUND

Charged-particle beams are among the most advanced methods currentlyavailable for the treatment of cancer tumors by radiotherapy. The morecommon charged-particle beam therapy centers use protons as the particleof choice, while a few centers have begun using heavy ion particles suchas carbon ion beams.

The specific advantage of charged-particle beam therapy in treatingtumors is the physical effect known as the “Bragg peak.” The Bragg peakis a sharp increase in delivered dose, which occurs near the end of aparticle trajectory in the patient. The physical characteristics of theBragg peak make it possible, in principle, to more carefully conform theparticle-beam to the shape of the tumor. In addition, since there isvery little beam intensity beyond the range of the Bragg peak, there canbe significant reduction in overall radiation dose to normal tissue, ascompared to photon external beam radiotherapy.

In order to make use of narrow tumor margins that are possible inprinciple with charged particle beams, it is necessary to have anaccurate knowledge of the beam penetration in the patient. The currentpractice is to infer the penetration of charged particles, based oninformation gathered from x-ray imagery, particularly computedtomography (CT). However, there are well-known problems with making theextrapolation from CT imagery to the expected penetration of chargedparticle beams, which leads to an uncertainty in the knowledge of thebeam penetration in the actual patient. In addition, the patient anatomycan change over time, leading to changes in the actual penetration ofthe charged particle beam from one treatment to the next, furtherleading to uncertainty in the knowledge of the actual delivered dose totumor and to normal tissue.

SUMMARY

The disclosed systems, methods, and devices address the uncertainty inbeam location by providing a means to determine particle beampenetration in a patient during the time frame of a daily treatment. Thedisclosed systems, methods, and devices may also be used to determinethe charged particle beam penetration in phantoms constructed frommaterials chosen to mimic the behavior of human tissue when exposed toradiation, often called “water-equivalent” materials. The disclosedsystems, methods, and devices improve the accuracy of determination ofcharged particle beam penetration in patients. The disclosed apparatusand methods also apply to the calibration of charged particle beams fortherapeutic use. This disclosure applies to all charged-particle beamtherapies for treating cancer.

Disclosed are a system, method, and apparatus that provide informationabout the trajectory of a charged particle beam as it traverses apatient undergoing external beam therapy. Although the presentembodiment primarily addresses proton beam therapy, it is alsoapplicable to other charged particle beams, and specifically to carbonatom beams.

A method is disclosed for determining charged-particle beam trajectoriesthrough the use of a variation of the charged-particle beam energy as afunction of time, and measurement of the yield of fluorescent radiationfrom fiducial markers as a function of time, and application of analgorithm to extract information on the beam trajectory. A “fiducialmarker” as used herein includes any material with a known compositionthat is placed at a known location. In particular, the fiducial markercan contain a material with x-ray fluorescence.

Also disclosed is a method to use a charged-particle beam in a way thatis compatible with its use for patient therapy. The charged-particlebeam excites atomic electrons in all of the materials along thecharged-particle beam path. These excited electrons leave behind an atomin an excited energy state, which is de-excited through a number ofprocesses. One of the processes is the production of fluorescent x-rays.

The method detects these fluorescent x-rays, and uses the intensity ofthe fluorescence, along with other information, to determine thetrajectory of the charged-particle beam in the patient. The energy ofthe fluorescent x-ray can be selected such that the x-ray can readilypass through the patient's tissue and reach the detector. For example,the energy of the fluorescent x-ray can be at least 20 keV (e.g., atleast 30 keV, at least 40 keV, at least 50 keV, at least 60 keV, atleast 70 keV, at least 80 keV, at least 90 keV, at least 100 keV, atleast 110 keV, at least 120 keV, at least 130 keV, or at least 140 keV).In some embodiments, the energy of the fluorescent x-ray can be 150 keVor less (e.g., 140 keV or less, 130 keV or less, 120 keV or less, 110keV or less, 100 keV or less, 90 keV or less, 80 keV or less, 70 keV orless, 60 keV or less, 50 keV or less, 40 keV or less, or 30 keV orless). The energy of the fluorescent x-ray can range from any of theminimum energies described above to any of the maximum energiesdescribed above. For example, the energy of the fluorescent x-ray canrange from 20 keV to 150 keV (e.g., from 20-40 keV, from 40-50 keV, from50-60 keV, from 60-80 keV, or from 60-90 keV).

By using fluorescent x-rays, the method takes advantage of the narrowline-width and high detection efficiency of x-rays of atomic origin. Theline-width of the fluorescent x-ray can be sufficiently narrow, suchthat the fluorescent x-ray can be readily detected without interferencefrom a wide range of x-rays from other processes that do not providebeam position information. Suitable line-widths for the fluorescentx-ray line-width can be selected in view of the detector or detectorsconfigured to measure the fluorescent x-ray. For example, the line-widthof fluorescence x-rays can be approximately 100 eV for high-resolutionsolid-state detectors, or a few hundred eV for proportional counters. Incertain embodiments, the line-width of the fluorescent x-ray is 1 keV orless (e.g., 900 eV or less, 800 eV or less, 700 eV or less, 600 eV orless, 500 eV or less, 400 eV or less, 300 eV or less, 300 eV or less, or100 eV or less). The line-width of the fluorescent x-ray can besufficiently narrow to permit the separation of lines from differentelements and/or different inner-shell atomic energy levels, such as theK and L shell of the element gold (Au).

A number of materials can be selected to create fiducial markers thatwill produce fluorescent x-rays that will pass through the body with lowattenuation but have a high detection efficiency. The fluorescent x-rayis produced by atomic de-excitation. The chemical element used as afiducial marker can be selected to be compatible with human use and withradiotherapy. In some embodiments, the method uses gold (Au) fiducialmarkers, which produce K-shell fluorescent x-rays of an energy andline-width of 60-80keV, which is suitable for detection during clinicalprocedures. Other atomic elements can also produce suitable x-rays, andthe use of these other elements is included in the scope of theinvention. Suitable materials for producing these fluorescent x-raysinclude materials used commonly in medicine and as contrast agents,including gold (Au), gadolinium (Gd, with K shell transition radiationin the range of 42-50 keV), iridium (Ir, with K shell transitionradiation in the range of 63-76 keV), iodine (I, with K shell transitionradiation in the range of 28-33 keV), xenon (Xe, with K shell transitionradiation in the range of 29-33 keV), barium (Ba, with K shelltransition radiation in the range of 32-36 keV), lanthanum (La, with Kshell transition radiation in the range of 33-38 keV), samarium (Sm,with K shell transition radiation in the range of 40-45 keV), europium(Eu, with K shell transition radiation in the range of 41-47 keV),terbium (Tb, with K shell transition radiation in the range of 44-50keV), erbium (Er, with K shell transition radiation in the range of48-56 keV), thulium (Tm, with K shell transition radiation in the rangeof 50-58 keV), lutetium (Lu, with K shell transition radiation in therange of 53-61 keV), tungsten (W, with K shell transition radiation inthe range of 58-67 keV), rhenium (Re, with K shell transition radiationin the range of 58-69 keV), osmium (Os, with K shell transitionradiation in the range of 61-71 keV), and Platinum (Pt, with K shelltransition radiation in the range of 65-76 keV).

The method uses a known position of fiducial markers to identify theemission location of fluorescent x-rays. Implanted fiducial markers arecommon in radiotherapy, and specific examples are for prostate therapyand lung therapy. However, implanted fiducials can be used in many otherareas of the body for other types of cancer treatment, and these usesare included herein.

Fiducial markers are typically located by performing acomputed-tomography (CT) scan of the patient, which can also be usedwith the disclosed methods. However, other means to locate fiducialmarkers that can be used in the disclosed methods include highresolution sonography, radiography, and RF emission from markers withtransmitters.

Fiducial markers can take different physical forms, including metallicwires, helical coils, and surgical clips. For example, fiducial markerscommonly used in medical practice for marking tumor locations, such asthe Visicoil™ product and surgical clips made from gold can be used. Inaddition to these common fiducial markers, the method incorporates theuse of other suitable classes of fiducial markers which contain x-rayfluorescent atoms, such as nanoparticles, metal-conjugated proteins, andimaging contrast agents. For example, fiducial markers may also take theform of injected liquids containing atoms that fluoresce in the energyranges described above (e.g., emit a fluorescent x-ray having an energyof from 20-150 keV). Examples of such injectable fiducial markersincludes nanoparticles formed from a suitable x-ray fluorescing material(e.g., gold nanoparticles, gadolinium nanoparticles, gold-gadoliniumnanoparticles, core-shell nanoparticles containing a suitable x-rayfluorescing material in the core and a shell formed from a passivatingmaterial such as a polymer), microcontainers encapsulating a solution ofa suitable x-ray fluorescing material (e.g., polymer tubes or capsulesfilled with, for example, a gadolinium solution), and radium containingradiopharmaceuticals.

The method uses a particular protocol for delivering the particle beamat any time prior to, during, or after treatment of a patient, in orderto determine the trajectory of the beam within the patient. The particlebeam is delivered with a known beam energy, which is varied, whilemeasuring fluorescence emission from implanted fiducial marker(s) insynchrony with the variation of the beam energy. The variation of thebeam energy produces a change in the depth of penetration of the chargedparticle beam, which is reflected in a variation of the detectedfluorescence emission.

In some embodiments, the method involves the detection of an x-ray of asingle energy. Attenuation of the emitted fluorescent beam can in someembodiments be affected by variations in the patient's body thicknessand composition, which may not be independently determinable. Therefore,in other embodiments, the method uses the simultaneous detection ofx-rays of two or more different energies. These x-rays originate at thesame location in the patient. Since the x-rays have two differentenergies, they will travel through the patient's body with differentlevels of attenuation. The two (or more) x-ray energies will be detectedby an energy selective x-ray detector. A suitable method for thisdetection is a pulse-height analysis system, such as a silicon orgermanium detector, or in some cases, a scintillation counter system.Other methods of detecting the number of x-rays emitted within eachenergy channel are known, and may be used in the disclosed systems,methods, and devices.

By simultaneously detecting x-rays of more than one energy, it ispossible to determine the ratio of the intensity of these beams that aredetected. The method will work with two or more beams. In someembodiments, the K-α (near 80 keV, also called KN radiation) and K-βshell fluorescence (near 68 keV, also called KL radiation) from Au(gold) fiducials is used. However, other materials are suitable for thispurpose, including in certain cases materials that occur naturally inthe human body. Materials commonly used in medicine such as gadolinium,iodine, iridium, and radium have suitable energy levels that areseparated by several keV and can be distinguished by suitable detectors,including solid-state detectors.

Both of the x-ray beams, e.g., K-α and K-β, pass through the sameregions of the patient. Each individually experiences intensityattenuation that is a function of the energy of the x-ray beam. Theenergy of the beam is measured. The energy of the x-ray beam identifiesthe type of the beam, e.g., that it is a K-α or an K-β shell beam. Withthe knowledge of the type of beam, e.g., K-α or K-β shell, the ratio ofthe intensity of these beams can then be used to determine theattenuation thickness of the patient that the beams have traversed. Thisis accomplished by using a formula for x-ray attenuation based on anexponential function, in which the effective thickness of the materialtraversed is multiplied by the attenuation coefficient for the specificbeam, e.g., the K-α or K-β shell. The attenuation coefficients caneither be taken from widely known tabulated information, or determinedmore specifically by measurements on so-called “phantom” materialsselected to mimic human tissue. The relative intensity of the beams isused with the knowledge of the exponential attenuation law to correctthe information of x-ray intensity that is used to determine the protonenergy and range.

The disclosed method can incorporate an algorithm for determiningparticle beam trajectory based on the synchronous variation of incidentparticle beam energy and fluorescence emission intensity. The disclosedmethod may also be used to adapt a therapeutic particle-beam therapybased on information revealed by application of the disclosed method, soas to improve the conformality of the particle-beam and the tumor beingtreated.

Energy detectors (e.g., multi-energy detectors) may be arranged atvarious locations around the patient to increase the number of beamsthat are measured, thereby reducing the time needed to complete ameasurement, and to increase the accuracy of the measurement.Fluorescence x-rays may also be measured over a substantial part of thespherical solid-angle surrounding the fiducial markers using wide-angledetectors, so as to increase signal detection efficiency and reducepatient dose. As a beneficial alternative, the method allows for the useof collimated detectors in an angular arrangement, so as to determinethe location of emission of fluorescence x-rays without the need forother determination of their position.

An apparatus and system are disclosed that comprise a source ofcharged-particles with an energy that can be varied as a function oftime, fiducial markers with a constituent material that produces afluorescence signal suitable for detection at a distance removed fromthe treatment field, an arrangement of detectors to measure thefluorescence signal as a function of time, and suitable computer controland electronic equipment to implement the method and apply the disclosedalgorithm to extract and display information on the charged-particlebeam trajectory.

The apparatus and system can incorporate a therapeutic charged-particlebeam with an energy that is varied. Typically this is accomplished witha “modulation wheel”, also called a “propeller”. Implanted fiducialmarkers containing a high density of atoms of the desired element toproduce fluorescence x-rays may be placed in or near the tumor treatmentlocation. Fluorescence detectors may be arranged outside the patient soas to be outside the path of the incident particle beam, but areotherwise located close to the patient's skin surface to enhance signaldetection.

Fluorescence signals may be measured from the detectors, and selectedaccording to their energy using pulse-height discrimination techniques.The energy of fluorescence can be determined by the element used in thefiducial implant. This energy may be high enough so that large numbersof x-rays are transmitted outside the patient. By using fiducial markersof the heavy element gold (Au), the marker is compatible with clinicaluse, and the fluorescence x-ray is well-separated from other sources ofbackground radiation.

A computer system can be used to record the intensity of emitted x-rayswhile monitoring the energy of the incident particle beam. An algorithm,e.g., derived from Monte-Carlo simulations, can be used to extract beamtrajectory from the measured emission intensity patterns.

An imaging detection system may be used to create a spatial map of thelocation of the emitted fluorescent x-rays, so as to more accuratelydetermine the location of protons that create the fluorescence. Thisspatial imaging detection system may be capable of sorting fluorescentx-rays according to their energy, and to use this information forattenuation correction as described above.

Also disclosed are method of treating cancer in a subject that involveimplanting fiducial markers in or near the cancer, determiningcharged-particle beam trajectories through the use of a variation of thecharged-particle beam energy as a function of time, measurement of theyield of fluorescent radiation from the fiducial markers as a functionof time, using an algorithm to optimize beam trajectory, and using theoptimized charged-particle beam to irradiate the cancer. Any cancer,e.g., solid tumor, that can be treated by charged-particle beamradiotherapy can be treated by this optimized method. For example, thecancer can be lung, prostate, breast, skull base tumors, or uvealmelanomas.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a schematic view of an apparatus according to an embodiment ofthe invention.

FIG. 2 is a table illustrating steps of a method in accordance with anembodiment of the current invention.

FIG. 3 contains a top graph of model variations of the charged particlebeam as a function of time and a bottom graph of the fluorescence yieldas a function of time, showing the response of the fiducial marker inaccordance with an embodiment of the invention.

FIG. 4 is a schematic of an experimental design to determine whetherproton-induced x-ray fluorescence can be utilized to determineclinically important dosimetric parameters during a proton therapytreatment.

FIG. 5 is a graph showing pulse height analysis of proton induced Aufiducial x-ray emission (counts as a function of energy, keV).

FIG. 6 is a graph showing analytical model of the experiment using Braggcurve approximations with stopping power parameters for Au adapted fromNIST data tables (fluorescence as a function of path length, cm).

DETAILED DESCRIPTION

In the following description, reference is made to the accompanyingdrawings, which form a part hereof, and which show, by way ofillustration, specific examples or processes in which the invention maybe practiced. Where possible, the same reference numbers are usedthroughout the drawings to refer to the same or like components. In someinstances, numerous specific details are set forth in order to provide athorough understanding of the invention. The invention, however, may bepracticed without the specific details or with certain alternativeequivalent devices and/or components and methods to those describedherein. In other instances, well-known methods and devices and/orcomponents have not been described in detail so as not to unnecessarilyobscure aspects of the invention. For the sake of clarity, the variouselements represented in the figures are not necessarily to scale.

FIG. 1 is a schematic of one embodiment of the disclosed apparatus. Asource of high energy charged particles 103 produces a beam of particles106, which is directed at a target 101. In a preferred embodiment, thecharged particles are protons with energy ranging from 50 MeV to 250MeV, but other charged particles and energy ranges may be used. Forexample, the method is suited to be used with helium and carbon atomparticle beams, both of which are used in practice for medicaltreatment.

The target 101 contains one or more, e.g., plurality, of fiducialmarkers 102 which are placed at fixed locations within the target. Inthe embodiment in which the target is a patient, these fiducial markersmay preferably be clinically approved seeds manufactured from gold, withdimensions of approximately 1 mm diameter, as commonly used for prostateimplant radiotherapy. One example type of suitable gold fiducial markeris the Visicoil™, which can range in diameter from 0.35 mm to 1.10 mmand length from 0.5 cm to 3 cm. Other suitable markers include goldmarkers used to define tumor locations with the Cyberknife™ radiosurgerysystem (wherein the gold markers are 0.8 mm×5 mm in size), and surgicalclips used to mark tumor boundaries.

In the embodiment in which the target is a phantom, the fiducial markersmay also be composed of gold wire, with preferable dimensions of 1 mmdiameter by 5 mm length.

The incident charged particle beam may be directed towards the targetand the fiducial markers, with an energy that changes as a function oftime in a known way. The control of particle beam energy is arequirement of particle radiotherapy, and the means to accomplish thisare well known to practitioners of the art.

When the energy of the particle beam 106 is sufficiently high enough,the Bragg peak will approach the location of the fiducial markers 102,which will begin to produce fluorescence radiation 104.

The fluorescent radiation emitted by the fiducial markers contains oneor more identifiable core-level x-ray emission peak characteristic ofthe atomic composition of the fiducial. In some embodiments, a majorelemental component of the fiducial marker is gold (Au), which emits Kshell fluorescent x-rays in the range of approximately 68-80 keV, whichare sufficient to travel through the target to reach the detectors 105without excessive attenuation. In some embodiments, both K and L shellfluorescence from Au (gold) fiducials is used.

The fluorescent radiation 104 is not directed into any specificdirection. To efficiently collect the radiation, a plurality of x-raydetectors 105 (e.g., multi-energy detectors) can be arranged around thetarget. In FIG. 1 three such detectors are shown, but more or fewerdetectors can be used.

In some embodiments the detector 105 is a scintillation detector, butother detectors of x-ray radiation are known to practitioners skilled inthe art and can be used herein. These include solid state energydispersive detectors, commonly called silicon (Si) and germanium (Ge)detectors, proportional counters, gas-electron multiplier detectors,energy-dispersive detectors, and wavelength dispersive detectors.

The detector 105 produces one or more electrical signals whose amplitudeis proportional to the energy of the x-ray 104 that reaches thedetector. To enhance the signal-to-noise ratio, pulse-height analysismay be used on the detector signal to isolate the signal from the x-raysoriginating from the fiducial markers. The fiducial markers producecharacteristic x-rays which are sufficiently far from the x-raysproduced by other materials in the patient or the phantom, that there islittle interference to the desired fiducial signal from other materials.

FIG. 2 is a diagram illustrating steps of one embodiment of thedisclosed methods. The method can begin with the implantation offiducial markers in the target, 201. In some embodiments, the target iseither a patient, or a phantom selected for quality-assurance of thecharged-particle treatment beam 103-106. In the embodiment in which thetarget is a patient, the fiducial markers may be similar to thosealready in clinical use for treatment of prostate cancer or lung cancer.

The location of the fiducial markers is identified in the next step ofthe method, 202. In the case in which the target is a phantom, thelocation of the markers may be accomplished by the construction of thephantom, or by optical means, or other means well-known to thosepracticed in the art. In the case in which the target is a patient, thefiducial markers by be localized using an x-ray computed-tomography (CT)scan. Other methods of localizing the fiducial markers, such asradiography, radio-frequency emitters coupled to fiducials, magneticresonance imaging, or ultrasound, may also be used.

The particle beam 106 may be prepared at a specific energy, and directedat the target, step 203. The yield of fiducial marker fluorescencex-rays can be measured 204 and recorded. Optionally, two or morefluorescent energies are detected to correct for attenuation asdescribed above. The energy of the beam 106 can be incremented,resulting in a stepwise variation of the beam energy with time, with theprecise relationship of time and beam energy being known. The beamenergy can be compared to the desired endpoint, 205, and the cycle ofmeasurement of x-rays and incrementing beam energy (203, 204, 205) canbe repeated until the entire range of particle energies is scanned.

An algorithm 206 can be applied to the measured fluorescence data as afunction of time, to determine the precise time at which the particlebeam reached the known location of the fiducial markers. This time inturn can be converted into a beam energy, which was recorded in steps203-205.

In some embodiments, the algorithm used to process the fluorescence datais based on accurate measurements made with proton beams and fiducialmarkers in a water-equivalent phantom. From this measurement, a profilecan be determined that represents the intensity distribution offluorescence from the fiducial as the Bragg peak sweeps across thefiducial marker. The specific point in the profile that represents thelocation of the fiducial can thus be accurately determined. Thisinformation can be used by the algorithm to extract the location of theparticle beam Bragg peak in the target from the measured intensity offluorescence x-rays as a function of time.

As an illustration of the process of the algorithm, FIG. 3 (301) shows amodel graph (top) of the variation of the charged particle-beam energyas a function of time, exhibiting a monotonically increasing behavior.The energy of the beam is known at any time. The emitted fluorescenceyield from a single fiducial marker is illustrated in the bottom graphof FIG. 3 (302). An edge-like structure occurs at the location of thetime t* (303), highlighted by the vertical dashed line. The shape of theedge structure is analyzed to determine the precise time, t*, whichcorresponds to the particle beam Bragg peak maximum encountering thefiducial marker. Since time also determines beam energy (301), it isthen known at which beam energy the particle beam strikes the fiducials.

The results of the algorithm are presented in a suitable form in thefinal step of the method 207. Specific parts, shapes, materials,functions and modules have been set forth, herein. However, a skilledpractitioner will realize that there are many ways to fabricate thedisclosed system, and that there are many parts, components, modules orfunctions that may be substituted for those listed above.

Also disclosed are method of treating a tumor in a subject that involveimplanting fiducial markers in or near the cancer, determiningcharged-particle beam trajectories through the use of a variation of thecharged-particle beam energy as a function of time, measurement of theyield of fluorescent radiation from the fiducial markers as a functionof time, using an algorithm to optimize beam trajectory, and using theoptimized charged-particle beam to irradiate the cancer. Any tumor,e.g., cancer, that can be treated by charged-particle beam radiotherapycan be treated by this optimized method. For example, the cancer can belung, prostate, breast, skull base tumors, or uveal melanomas. In someembodiments, the fiducial markers are placed at around the tumormargins, at one or more locations inside the tumor, or a combinationthereof.

The term “subject” refers to any individual who is the target ofadministration or treatment. The subject can be a vertebrate, forexample, a mammal. Thus, the subject can be a human or veterinarypatient. The term “patient” refers to a subject under the treatment of aclinician, e.g., physician.

The term “treatment” refers to the medical management of a patient withthe intent to cure, ameliorate, stabilize, or prevent a disease,pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder.

The term “tumor” or “neoplasm” refers to an abnormal mass of tissuecontaining neoplastic cells. Neoplasms and tumors may be benign,premalignant, or malignant. The term “cancer” refers to a cell thatdisplays uncontrolled growth, invasion upon adjacent tissues, and oftenmetastasis to other locations of the body.

While the above detailed description has shown, described, and pointedout the fundamental novel features of the invention as applied tovarious embodiments, it will be understood that various omissions andsubstitutions and changes in the form and details of the componentsillustrated may be made by those skilled in the art, without departingfrom the spirit or essential characteristics of the invention.

EXAMPLES Example 1 Proton Induced X-Ray Fluorescence for In-VivoDetermination of Proton Range and Energy

FIG. 4 illustrates the experimental design used to determine whetherproton-induced x-ray fluorescence can be utilized to determineclinically important dosimetric parameters during a proton therapytreatment.

Measurements. Therapeutic beams from the UF Proton Therapy Institutewere used to excite proton induced x-ray fluorescence emission (PIXE)from cylindrical pure gold fiducial markers. The markers were embeddedin a homogeneous water phantom and PIXE was measured using NaIscintillators with energy dispersive spectral analysis. The geometry ofthe phantom and marker placement was chosen to model parallel-opposedbeam treatment of prostate cancer by proton therapy.

Modelling. An analytical model of fluroescence yield in realistictherapy conditions was developed using semi-empirical Au K and L shellcross-sections for proton induced emission, and attenuation data forboth xray channels. The fluorescence yield from these markers wasfurther modeled using the GEANT4 Monte-Carlo package with low-energycorrections.

Measurements were made with proton beam maximum energy ranging from 80MeV to 200 MeV. The pure gold fiducial was placed at a fixed depth in awater tank. The gold K and L shell x-rays passed through 13.5 cm ofwater and the wall of the acryllic tank before reaching a 2 cm diameterNaI scintillator where they were detected and energy scaled using pulseheight analysis (FIG. 5).

Backgrounds were taken with no beam and no gold sample, and with aproton beam but no gold sample. The pulse-height analysis spectrum wasaccumulated in a multichannel analyzer, and calibrated using a Cs-137source.

An analytical model of the experiment was developed using the Braggcurve approximations of Bortfeld [Med. Phys. 24 (1997) 2024-2033] withstopping power parameters for Au adapted from NIST data tables (FIG. 6).The model incorporates range straggling and energy spread, and fluencereduction due to inelastic nuclear events, using a parameterization tofit data of Janni [At. Data Nucl. Data Tables 27 (1982) 147-339].

PIXE from gold fiducial markers was readily detected above backgroundusing conventional NaI-Tl scintillation detectors, in a clinical therapyproton beam. This work shows the feasibility of using PIXE for in-vivodosimetry with proton therapy.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1. A method for improving the trajectory of charged-particle beams usedin cancer therapy in a subject comprising: (a) placing in a subject oneor more fiducial markers that produce fluorescent x-rays of one or moredistinct energies when struck by a charged-particle beam; (b)determining the locations of the one or more fiducial markers; (c)changing as a function of time the energy of a charged-particle beamwhich impinges on the subject; (d) recording as a function of timefluorescent x-ray emissions from the fiducial markers when the subjectis struck by the charged-particles; (e) applying an algorithm to therecorded information to determine the location of the particle beam inthe target relative to the known locations of the fiducial markers; (f)processing the results of the algorithm in a form suitable for display;and (g) displaying location of the particle beam position relative tothe fiducial markers.
 2. The method of claim 1, further comprisingchanging the trajectory of the charged-particle beam based on themeasurement of particle beam induced fluorescence.
 3. The method ofclaim 1, wherein the one or more fiducial markers have a compositionwhich produces a first fluorescent x-ray in the energy range from 20 keVto 150 keV.
 4. The method of claim 1, wherein the one or more fiducialmarkers have a composition which produces a second fluorescent x-ray inthe energy range from 20 keV to 150 keV that is distinct from the firstfluorescent x-ray.
 5. The method of claim 4, further comprising usingthe ratio of the intensity of the first fluorescent x-ray and the secondfluorescent x-ray to determine the attenuation thickness of the patientthat the beams have traversed.
 6. The method of claim 4, wherein the oneor more fiducial markers have a substantial component of the elementgold (Au).
 7. The method of claim 1, wherein the fluorescent x-rayemissions are recorded using one or more scintillation detectors.
 8. Themethod of claim 7, wherein the one or more scintillation detectors havecollimation suitable to exclude substantial response to radiation notoriginating from the fiducial markers.
 9. A method of treating a tumorin a subject, comprising; (a) implanting one or more fiducial markers inor near the tumor; (b) identifying an optimize trajectory for acharged-particle beam using the method of claim 1; and (c) using theoptimized charged-particle beam to irradiate the cancer.
 10. The methodof claim 9, wherein the tumor is a lung cancer, prostate cancer, breastcancer, skull base tumor, or uveal melanoma.
 11. The method of claim 9,wherein the one or more fiducial markers are placed at one or more ofthe tumor margins, at one or more locations inside the tumor, or acombination thereof.
 12. A system for improving the accuracy of acharged-particle beam used in cancer therapy comprising: (a) a source ofcharged-particles of suitable energy for therapeutic effect which can bevaried in energy as a function of time; (b) one or more fiducial markersthat produce fluorescent x-rays of one or more distinct energies whenstruck by a charged-particle beam; (c) one or more fluorescent energydetectors suitable for measuring fluorescent x-rays emitted by thefiducial markers; (d) a recorder suitable to record the energy of thecharged-particle beam and the fluorescent x-ray emissions as a functionof time; (e) a processor and memory to calculate penetration of thecharged-particle beam in the target based on the recorded information;and (f) a display by which the information on penetration is presentedin suitable form.
 13. The system of claim 12 wherein the fiducialmarkers have a composition which produces a fluorescent x-ray in theenergy range from 20 keV to 150 keV.
 14. The system of claim 12, whereinthe fiducial markers have a composition which produces a secondfluorescent x-ray in the energy range from 20 keV to 150 keV that isdistinct from the first fluorescent x-ray.
 15. The system of claim 14,wherein the fiducial markers have a substantial component of the elementgold (Au).
 16. The system of claim 12, wherein the one or morefluorescence energy detectors are scintillation detectors.
 17. Thesystem of claim 16, wherein the one or more fluorescence energydetectors have collimation suitable to exclude substantial response toradiation not originating from the fiducial markers.